1. Field of the Invention
This invention relates to a process for producing L-aspartyl-L-phenylalanine alkyl, aryl or aralkyl esters.
2. Description of the Prior Art
L-aspartyl-L-phenylalanine esters are peptides which have been noted as sweeteners in recent years. L-aspartyl-L-phenylalanine methyl ester (abbreviated as APM hereinafter) is a well known example of such a sweetener.
It is well known that the process for production of APM includes both chemical and enzymatic synthetic processes.
The chemical synthetic process for the production of APM comprises condensing N-protected L-aspartic acid anhydride and L-phenylalanine methyl ester (abbreviated as PM hereinafter) to obtain N-protected APM from which the protective group is subsequently removed. The enzymatic synthetic process comprises allowing a protein-decomposing enzyme to act on an N-protected L-aspartic acid and PM to obtain N-protected APM, or the PM adduct of N-protected APM, and then removing the protective group to form APM. However, both processes require the complicated steps of introducing and removing protective groups.
A process is also known for producing APM without using protective groups (see Japanese Patent Kokai No. 126796/1983, "Digests of the Publications at the Annual Meeting of the Agricultural Chemical Society of Japan" in 1983, p. 42). This process is a microbiological synthetic process which uses a microorganism selected from one of the following genuses: Pseudomonas, Torulopsis, Rhodotorula, and Sporobolomyces. This process, however, is not always suitable for the industrial production of APM because it produces extremely low yields.
The present inventors have previously found that by employing microorganisms, one can bring about the direct and effective formation of APM from L-aspartic acid and PM (see Japanese Patent Application No. 75559/1983).
However, a major drawback associated with processes for producing aspartyl-phenylalanine esters using as a starting material unprotected L-aspartic acid is the fact that the reaction forming APM from L-aspartic acid and PM is an equilibrium reaction, and this equilibrium prevents the substrates from being converted efficiently to aspartyl-phenylalanine ester products.
Therefore, a need continues to exist for a process providing for the efficient conversion of unprotected L-aspartic acid in reaction with L-phenylalanine esters to produce L-aspartyl-L-phenylalanine ester products in good yields.